- A REEXAMINATION OF THE RETRO-FRIES REARRANGEMENT OF SOME o-HYDROXYKETONES
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The retro-Fries rearrangement, catalyzed by protic and Lewis acids, was studied for some o-hydroxyketones.The results are consistent with the mechanism of an heterolytic cleavage and rearrangement.It appears that, in general, Lewis acids do not induce the retro-Fries rearrangement of o-hydroxyketones.However, in certain cases, it may be brought about the presence of a protic acid generated in situ, from a solvent-catalyst interaction.
- Martin, Robert,Lafrance, Jean Ronald,Demerseman, Pierre
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p. 539 - 548
(2007/10/02)
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- Model Studies for a Molecular Mechanism of Action of Oral Anticoagulants
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Warfarin , a potent oral anticoagulant agent, is known to inhibit the enzyme vitamin K epoxide reductase.The molecular mechanism of inhibition, however, is not known.It is proposed that the two major classes of oral anticoagulants, the 3-substituted-4-hydroxycoumarins and the 2-substituted-1,3-indandiones, are mechanism-based inactivators of this enzyme.The proposed mechanism of inactivation involves enzyme-catalyzed activation of the oral anticoagulants by tautomerization to the hypothetically reactive diketo forms which then undergo attack by active-site nucleophiles.In order to test the chemistry of this proposal, it is shown that the two classes of oral anticoagulants are unreactive toward bases and nucleophiles (except for deprotonation), until they are electrophilically substituted at the 3-position of the coumarins or at the 2 position of the indandiones.These model compounds for the proposed enzyme-generated reactive intermediates, then, are shown to be highly reactive toward a variety of nucleophiles and support the hypothesis that the oral anticoagulants are converted by vitamin K epoxide reductase into reactive compounds which can acylate an active-site nucleophile and thereby inactivate the enzyme.
- Silverman, Richard B.
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p. 3910 - 3915
(2007/10/02)
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